Tumoral heterogeneity is associated with more aggressive tumor phenotype and poor clinical outcome. Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease. The treatment of stage III NSCLC involves a multi-disciplinary approach and careful patient selection to determine which resectable patients might benefit from trimodality therapy (TMT). TMT includes neoadjuvant chemotherapy (NAC) followed by surgery. NAC administered prior to surgery can reduce tumor extent and metastases, thereby improving resectability. The role of surgery in stage IIIA patients is, however, controversial. Survival benefit of surgery in this setting has been difficult to demonstrate in multi-institute trials compared to definitive chemoradiation. The effectiveness of TMT is variable. Major pathologic response (MPR), defined as <=10% residual tumor, is strongly associated with improved overall survival (OS) following NAC. However, there are no clinically validated biomarkers to predict MPR. Existing patient selection approaches are based on anatomic and physiologic criteria. For example, in existing clinical practice, the selection of patients for TMT is based on relatively limited lymph node burden, single lobe involvement, and patient fitness, with little or no attention paid to specific markers of response. Thus, existing approaches suffer from low accuracy, intra-observer variability, as well as inter-observer variability, and are sub-optimal.